Project Summary: Behavioral Inflexibility and Dorsal Striatal AMPA Receptors (BIDSAR) Alcohol use problems may emerge from behavioral inflexibility, including difficulties processing information about conflicting goals such as seeking alcohol's rewarding effects while avoiding its aversive ones, and/or shifts towards habitual, stimulus-bound drinking. However, unknown is the extent to which behavioral inflexibility predisposes an individual toward risky alcohol drinking, if chronic voluntary alcohol drinking mediates shifts in behavioral flexibility, or by what neural mechanisms behavioral flexibility is mediated. In short, there remains a critical gap in our understanding of the genetic and neural mechanisms underlying inflexible alcohol drinking. There is a critical need to understand the mechanisms underlying both an innate proclivity towards, and the effects of alcohol on, behavioral inflexibility, with a long-term goal of developing novel treatments for excessive drinking behavior. The objectives of this application are to (1) to determine whether innate differences in inflexible behavior generalize to consumption of other reinforcers (e.g. saccharin) and to other cognitive domains (i.e., attentional set-shifting); (2) assess whether long-term alcohol drinking to intoxication in susceptible populations facilitates inflexible and compulsive-like behavior; and (3) determine whether either innate or acquired inflexible behavior is associated with altered AMPA receptor expression and pharmacology in the dorsolateral versus dorsomedial striatum, consistent with the idea of heightened glutamatergic tone. We will achieve the objectives by exploring these relationships using genetic mouse models of excessive alcohol drinking. Our central hypothesis is that cognitive inflexibility (compulsivity) is both an endophenotype and consequence of chronic alcohol consumption, mediated by altered prefrontal cortical glutamatergic input to the dorsal striatum.